Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders in the U.S. It is caused by mutations in the genes encoding polycystins, which are a family of proteins that include polycystin-1 (PC1), polycystin-2 (PC2) and probably other polycystin(s). Recently, we have identified the functions of two members of this class of proteins, PC2 and polycystin-L (PCL). We have established that both PC2 and PCL are Ca2+-permeable cation channels that are transiently activated by intracellular Ca2+ (Cai) and extracellular Ca2+ (Cao). They are also permeable to Na+, K+, NH4+ and other cations. We also found that naturally occurring mutant PC2 channels are not activated by increases in Cai and show other functional abnormalities. We hypothesize that with their high permeability and sensitivity to Ca2+ the PC channels may play a major role in transmembrane Ca2+ transport as well as in Ca2+ signaling and homeostasis. Through their sensitivity to changes in Cai the polycystin channels may participate in the control of a number of Ca2+-dependent cellular processes, including morphogenesis, cell proliferation, differentiation and apoptosis. PC2 interacts with PC1, which is associated with cadherin and integrin-related extracellular matrix. Mutations in the polycystin genes may disturb their functions in mediating transmembrane ion fluxes and lead to defective Ca2+ signaling, which, in turn, could result in abnormalities in the above-mentioned cellular processes as well as in disturbed tubular transport - central features of the pathogenesis of ADPKD. Recent studies have demonstrated that the polycystin channels play an important role in ciliary processes. Disturbance in these processes may also contribute to the pathophysiological mechanisms in ADPKD. The overall goal of this project, therefore, is to study polycystin channel activities in kidney cells affected in ADPKD and their modulation by changes in Cai and Ca2+-dependent signaling pathways. The following Specific Aims will be pursued: 1) To determine the regulation of polycystin channels by changes in Cai, Ca2+-dependent signal transduction pathways and cytoskeleton in cilia-containing kidney cells;and 2) To evaluate the functional relationships between Cao, polycystin channel activity, cadherin and integrin. In the long term, these studies should help understanding the pathophysiological mechanisms underlying ADPKD and developing new treatment modalities.